The function of TEAD1 in cardiac fibroblast activation [ChIP-Seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE253118 | GEO | 2024/01/15
REPOSITORIES: GEO
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Project description:Cardiac fibroblasts (CFs) are the primary cells tasked with depositing and remodeling collagen and significantly associated with heart failure (HF). TEAD1 has been shown to be essential for heart development and homeostasis. However, endogenous fibroblast TEAD1 in cardiac remodeling remains incompletely understood. Transcriptomic analyses revealed consistently upregulated cardiac TEAD1 expression in mice 4 weeks after transverse aortic constriction (TAC) and Ang-II infusion. Further investigation revealed that CFs were the primary cell type expressing elevated TEAD1 levels in response to pressure overload. Conditional TEAD1 knockout was achieved by crossing TEAD1-floxed mice with CFs- and myofibroblasts-specific Cre mice. Echocardiographic and histological analyses demonstrated that CFs- and myofibroblasts-specific TEAD1 deficiency and treatment with TEAD1 inhibitor, VT103, ameliorated TAC-induced cardiac remodeling. Mechanistically, RNA-seq analysis identified Wnt4 as a novel TEAD1 target. TEAD1 has been shown to promote the fibroblast-to-myofibroblast transition through the Wnt signalling pathway, and genetic Wnt4 knockdown inhibited the pro-transformation phenotype in CFs with TEAD1 overexpression. Furthermore, co-immunoprecipitation combined with mass spectrometry, chromatin immunoprecipitation, and luciferase assays demonstrated interaction between TEAD1 and BET protein BRD4, leading to the binding and activation of the Wnt4 promoter. In conclusion, TEAD1 is an essential regulator of the pro-fibrotic CFs phenotype associated with pathological cardiac remodeling via the BRD4/Wnt4 signalling pathway.
2023-12-28 | GSE251976 | GEO
Project description:Cardiac fibroblasts (CFs) play a crucial role in cardiac remodeling, which is a common cause of heart failure (HF). However, the molecular mechanisms underlying the transformation of fibroblasts into myofibroblasts remain largely unknown. Foxm1 is well-known in various cardiovascular diseases. However, the role of Foxm1-driven CF activation in the progression of cardiac remodeling towards HF is still being investigated. In this study, we observed an upregulation of Foxm1 expression in samples obtained from patients with heart failure (HF) and in mice with transverse aortic constriction (TAC)-induced cardiac remodeling. Additionally, we discovered that inhibition of Foxm1 using the drug FDI-6 improved TAC-induced cardiac remodeling and attenuated the activation of cardiac fibroblasts (CFs). Furthermore, through our investigations, we found that Foxm1 was activated in Tcf21-Cre and PostnMCM transgenic mice subjected to TAC surgery, resulting in the activation of CFs and exerting an influence on the cardiac remodeling process.
2024-05-10 | GSE248447 | GEO
Project description:Aims: Cardiac fibroblasts (CFs) play a crucial role in cardiac remodelling, which is a common cause of heart failure (HF). However, the molecular mechanisms underlying the fibroblast-to-myofibroblast transition remain largely unknown. Foxm1 is well known in various cardiopulmonary pathologies. However, Foxm1-driven CF activation in the progression of cardiac remodelling to HF remains to be investigated. Methods: Changes in Foxm1 expression were assessed in samples from patients with HF and mice with transverse aortic constriction (TAC)-induced cardiac remodelling. Pharmacologic antagonist FDI-6 was used to explore the effects of Foxm1 inhibition on post-TAC outcomes. Tcf21-Cre and PostnMCM were used to evaluate Foxm1 loss- and gain-of-function in CFs and myofibroblasts, respectively. Cardiac function and remodelling were examined by echocardiography and histological analysis. Foxm1 downstream target genes were identified by mass spectrometry (MS) and transcriptomic analysis. Post-translational regulation was evaluated by in vitro chromatin immunoprecipitation, co-immunoprecipitation, and ubiquitination assays. Pharmacological inhibition of Usp10 or knockout of p38γ in vivo verified the signalling pathway by which Foxm1 regulated cardiac remodelling. Results: Foxm1 was upregulated in human HF samples as well as in the mouse cardiac remodelling model. CFs were the primary cell type responsible for Foxm1 upregulation. Foxm1 pharmacological inhibition or genetic knockout in CFs or myofibroblasts significantly attenuated TAC-induced cardiac remodelling and HF. Conversely, conditional overexpression of Foxm1 in CFs or myofibroblasts resulted in more severe pathological cardiac remodelling and dysfunction. Combined RNA-sequencing and MS analysis revealed that Foxm1 promoted Usp10 expression by binding to its promoter. Usp10 interacted with p38γ, resulting in p38γ deubiquitination and thus influencing the downstream p38 mitogen-activated protein kinase (MAPK) signalling pathway. Pharmacological inhibition of Usp10 or genetic knockout of p38γ ameliorated the exacerbated TAC-induced cardiac remodelling in mice with myofibroblast-specific Foxm1 overexpression. Conclusion: Our findings reveal an essential role of Foxm1 in CF activation during cardiac remodelling. These results suggest that targeting the Foxm1/Usp10/p38γ MAPK axis may represent a new potential therapeutic strategy against pathological cardiac remodelling and HF.
2024-03-03 | PXD050281 | Pride
Project description:Aims: Cardiac fibroblasts (CFs) play a crucial role in cardiac remodelling, which is a common cause of heart failure (HF). However, the molecular mechanisms underlying the fibroblast-to-myofibroblast transition remain largely unknown. Foxm1 is well known in various cardiopulmonary pathologies. However, Foxm1-driven CF activation in the progression of cardiac remodelling to HF remains to be investigated. Methods: Changes in Foxm1 expression were assessed in samples from patients with HF and mice with transverse aortic constriction (TAC)-induced cardiac remodelling. Pharmacologic antagonist FDI-6 was used to explore the effects of Foxm1 inhibition on post-TAC outcomes. Tcf21-Cre and PostnMCM were used to evaluate Foxm1 loss- and gain-of-function in CFs and myofibroblasts, respectively. Cardiac function and remodelling were examined by echocardiography and histological analysis. Foxm1 downstream target genes were identified by mass spectrometry (MS) and transcriptomic analysis. Post-translational regulation was evaluated by in vitro chromatin immunoprecipitation, co-immunoprecipitation, and ubiquitination assays. Pharmacological inhibition of Usp10 or knockout of p38γ in vivo verified the signalling pathway by which Foxm1 regulated cardiac remodelling. Results: Foxm1 was upregulated in human HF samples as well as in the mouse cardiac remodelling model. CFs were the primary cell type responsible for Foxm1 upregulation. Foxm1 pharmacological inhibition or genetic knockout in CFs or myofibroblasts significantly attenuated TAC-induced cardiac remodelling and HF. Conversely, conditional overexpression of Foxm1 in CFs or myofibroblasts resulted in more severe pathological cardiac remodelling and dysfunction. Combined RNA-sequencing and MS analysis revealed that Foxm1 promoted Usp10 expression by binding to its promoter. Usp10 interacted with p38γ, resulting in p38γ deubiquitination and thus influencing the downstream p38 mitogen-activated protein kinase (MAPK) signalling pathway. Pharmacological inhibition of Usp10 or genetic knockout of p38γ ameliorated the exacerbated TAC-induced cardiac remodelling in mice with myofibroblast-specific Foxm1 overexpression. Conclusion: Our findings reveal an essential role of Foxm1 in CF activation during cardiac remodelling. These results suggest that targeting the Foxm1/Usp10/p38γ MAPK axis may represent a new potential therapeutic strategy against pathological cardiac remodelling and HF.
2024-03-10 | PXD050300 | Pride
Project description:Purpose: Cardiac fibroblasts (CFs) contribute to pathological remodeling by proliferating and secreting extracellular matrix. In contrast, physiological remodeling is an adaptive response to excessive demands of exercise that results in increased heart size without accompany fibrosis or deterioration of cardiac function. We hypothesize that these divergent outcomes are partially a function of cell-autonomous and paracrine cardioprotection afforded by CFs specifically during physiological remodeling. Our objective is to define the gene expression program (GEP) of CFs isolated from mouse models of physiological (swim) and pathological (thoracic aortic constriction (TAC) or myocardial infarction (MI)) remodeling to identify novel mechanisms underlying the development of pathological cardiac fibrosis and the cardioprotective benefits of exercise. Methods: Cardiomyocytes (CMs) were isolated by gravity sedimentation and CFs were isolated by differential plating for 2 hours from single-cell suspensions of 10-14 week old male C57BL/6 hearts subjected to the following 7 conditions: sedentary CFs (n=3), sham surgery CFs (n=2), 3 day TAC CFs (n=3), 10 day TAC CFs (n=3), 4 day swim CFs (n=3), 10 day swim CFs (n=3), and 5 day MI CFs (n=2). CMs were isolated from sedentary 10-14 week old male C57BL/6 hearts (n=3). Total RNA was isolated using the Qiagen RNeasy Plus Kit and genomic DNA removed using Qiagen gDNA columns. RNA quality was assessed with the Agilent Bioanalyzer and only samples with RIN >8.5 were used for sequencing. Library construction was performed using the TruSeq Stranded mRNA Sample Preparation Kit from 100ng poly-A mRNA. An Illumina HiSeq 2500 was used to generate 20-25 million single end reads of 100nt for each sample. The sequence reads that passed quality filters (Trimmomatic-0.32) were analyzed at the transcript isoform level using STAR_2.4.2a for SHRiMP_2_2_3 mapping to mouse genome assembly GRCm38.p4 version mm10 and processed with Cufflinks-2.0.2. Results: We determined that CFs display distinct GEPs that are inversely regulated in pathological and physiological remodeling. Spearman correlation and Principal Component Analysis (PCA) of genes with FPKM >1 and q >0.05 revealed consistency between biological replicates and highlighted active changes in GEPs during physiological and pathological remodeling both of which diverged from control samples in principal component (PC) 1 and PC2. CFs isolated from mice 5 days after initiation of MI also diverged from controls, TAC, and swim samples, demonstrating a different fibroblast GEP in ischemic and pressure overload induced remodeling. This analysis also revealed that our control models (sham surgery and sedentary) were indistinguishable from each other, therefore we typically treated sham and sedentary mice as a single control group in further studies. These initial results reveal that CFs differentially respond to pathological and physiological cues in as few as 3 days by enacting dynamic transcriptional changes in vivo. Consistent with previous reports of myofibroblast activation, Ingenuity Pathway Analysis (IPA) revealed that the most significantly enriched GO terms in pathological fibroblasts included stimulation of Rho-dependent contractile pathways and integrin-linked kinase (ILK) signaling, the latter of which was downregulated in a comparison between 10-day swim vs. control CFs. IPA transcription factor analysis comparing 10-day swim and 10-day TAC CFs further identified upregulation of detoxification and inflammatory transcription factors and downregulation of the serum response factor (SRF) after exercise. Furthermore, independent motif analysis using HOMER 2.0 identified the CArG box (SRF binding site) as the most enriched transcription factor binding site within 5kb of genes that are upregulated in 10-day TAC vs sham CFs. Conclusions: We have defined the GEPs of CFs that underlie physiological and pathological cardiac remodeling. Not only is the GEP of pathological CFs enriched in Rho-dependent pathways and SRF target genes, but the GEP of physiological CFs is enriched in detoxification and inflammatory target genes. We also demonstrate that the CFs change their transcriptional signature consistently and rapidly. Within 3-4 days of initiating extracellular stimuli, distinct profiles are observed in CFs isolated from swim-trained, pressure overload, or ischemic models of cardiac remodeling.
2018-03-14 | GSE89885 | GEO
Project description:Accumulation of activated cardiac fibroblasts plays a key role in heart failure progression. These cells deposit excessive extracellular matrix that leads to mechanical stiffness, myocyte uncoupling and ischemia. To investigate whether two developmentally distinct cardiac fibroblast populations exhibit distinct expression profiles in response to cardiac injury, and therefore might necessitate distinct therapeutic targeting, we performed microarray analysis on FACS sorted cells. Tie2cre lineage traced CFs, non Tie2cre lineage traced cardiac fibroblasts and endothelial cells were isolated from left ventricle of SHAM operated and banded hearts at the onset of fibrosis, one week after surgery. We used microarrays to detail the global programme of gene expression in cardiac fibroblasts and endothelium following pressure overload. Tie2cre lineage traced, non-tie2cre lineage traced fibroblasts and endothelial cells were sorted from left ventricle of 3 SHAM operated and 3 TAC operated adult male Black Swiss mice. Tie2cre lineage traced, non-tie2cre lineage traced fibroblasts and endothelial cells were sorted from left ventricle of 3 SHAM operated and 3 Transaortic Constriction (TAC) operated adult male Black Swiss mice for RNA extraction and Affymetrix microarray analysis. Hypertrophy in TAC animals, an lack of hypertrophy in SHAM operated animals, was evaluated by hemodynamic measurements before surgery and one week after surgery. Cells were isolated one week after surgery.
2014-05-19 | E-GEOD-45820 | biostudies-arrayexpress
Project description:Heart failure (HF) is a leading cause of morbidity and mortality. As adult cardiomyocytes (CMs) have little regenerative capacity, after myocardial infarction (MI), resident cardiac fibroblasts (CFs) synthesize extracellular matrix to form scar tissues, resulting in myocardial remodeling and HF. Thus, both cardiac regeneration and fibrosis are therapeutic targets for chronic MI. We previously reported that fibroblasts were directly reprogrammed into induced CMs (iCMs) by overexpression of cardiogenic transcription factors in vitro and in vivo in acute MI. Here we show that in vivo cardiac reprogramming generated iCMs from resident CFs, improved cardiac function, and reversed fibrosis in chronic MI using a novel transgenic mouse system. Single-cell transcriptome analysis revealed that cardiac reprogramming shifted matrix-producing CFs, matrifibrocytes, to a quiescent state and changed the interstitial cell landscape, suppressing fibrotic and inflammatory signatures and activating angiogenic program. Thus, in vivo cardiac reprogramming may be a promising approach for chronic HF.
2022-12-12 | GSE185265 | GEO
Project description:Accumulation of activated cardiac fibroblasts plays a key role in heart failure progression. These cells deposit excessive extracellular matrix that leads to mechanical stiffness, myocyte uncoupling and ischemia. To investigate whether two developmentally distinct cardiac fibroblast populations exhibit distinct expression profiles in response to cardiac injury, and therefore might necessitate distinct therapeutic targeting, we performed microarray analysis on FACS sorted cells. Tie2cre lineage traced CFs, non Tie2cre lineage traced cardiac fibroblasts and endothelial cells were isolated from left ventricle of SHAM operated and banded hearts at the onset of fibrosis, one week after surgery. We used microarrays to detail the global programme of gene expression in cardiac fibroblasts and endothelium following pressure overload. Tie2cre lineage traced, non-tie2cre lineage traced fibroblasts and endothelial cells were sorted from left ventricle of 3 SHAM operated and 3 TAC operated adult male Black Swiss mice.
2014-05-19 | GSE45820 | GEO
Project description:Cardiac fibroblasts (CFs) play critical roles in heart development, homeostasis, and disease. The limited availability of human CFs from native heart impedes investigations of CF biology and their role in disease. Human pluripotent stem cells (hPSCs) provide a highly renewable and genetically defined cell source, but efficient methods to generate CFs from hPSCs have not been described. Here, we show differentiation of hPSCs using sequential modulation of Wnt and FGF signaling to generate second heart field progenitors that efficiently give rise to hPSC-CFs. The hPSC-CFs resemble native heart CFs in cell morphology, proliferation, gene expression, fibroblast marker expression, production of extracellular matrix and myofibroblast transformation induced by TGFβ1 and angiotensin II. Furthermore, hPSC-CFs exhibit a more embryonic phenotype when compared to fetal and adult primary human CFs. Co-culture of hPSC-CFs with hPSC-derived cardiomyocytes distinctly alters the electrophysiological properties (EP) of the cardiomyocytes compared to co-culture with dermal fibroblasts (DFs). The hPSC-CFs provide a powerful cell source for research, drug discovery, precision medicine, and therapeutic applications in cardiac regeneration.
2019-02-08 | GSE126260 | GEO
Project description:BACKGROUND: Heart failure (HF) is one of the leading causes of mortality worldwide. Extracellular vesicles (EVs) including small EVs, or exosomes and their molecular cargo are known to modulate cell to cell communication during multiple cardiac diseases. However, the role of systemic EV biogenesis inhibition in the models of HF is not well documented and remains unclear. METHODS: We investigated the role of circulating exosomes during cardiac dysfunction and remodeling in a mouse transverse aortic constriction (TAC) model of HF. Importantly, we investigate the efficacy of Tipifarnib (Tip), a recently identified exosome biogenesis inhibitor that targets the critical proteins (Rab27a, nSmase2 and Alix) involved in exosome biogenesis for this mouse model of HF. In this study, 10-week-old male mice underwent TAC surgery, were randomly assigned to groups with and without Tip treatment (10 mg/kg three times/week) and monitored for 8 weeks and a comprehensive assessment was conducted through performed echocardiographic, histological, and biochemical studies. RESULTS: TAC significantly elevated circulating plasma exosomes and markedly increased cardiac left ventricular (LV) dysfunction, cardiac hypertrophy, and fibrosis. Furthermore, injection of plasma exosomes from TAC mice induced LV dysfunction and cardiomyocyte hypertrophy in uninjured mice without TAC. On the contrary, treatment of Tip in TAC mice reduced circulating exosomes to baseline and remarkably improved LV functions, hypertrophy, and fibrosis. Tip treatment also drastically altered the miRNA profile of circulating post-TAC exosomes, including miR331-5p which was highly downregulated both in TAC circulating exosomes and in TAC cardiac tissue. Mechanistically, miR331-5p is crucial for inhibiting fibroblast-to-myofibroblast transition by targeting HOXC8, a critical regulator of fibrosis. Tipifarnib treatment in TAC mice upregulated the expression of miR331-5p that acts as potent repressor for one of the fibrotic mechanisms mediated by HOXC8. CONCLUSIONS: Our study underscores the pathological role of exosomes in HF and fibrosis in response to pressure overload. Tipifarnib mediated inhibition of exosome biogenesis and cargo sorting may serve as a viable strategy to prevent progressive cardiac remodeling to HF.
2024-05-07 | GSE266185 | GEO